Molecular Mechanisms of C9ORF72-linked Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two devastating neurological disorders that share clinical, genetic and pathological overlap. The discovery of a hexanucleotide G4C2 repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene as a major cause of FTD and ALS confirmed the genetic link between these two neurodegenerative diseases, collectively referred to as C9FTD/ALS. Many different hypotheses about the possible pathogenic mechanisms of this repeat have been proposed, including haploinsufficiency leading to partial loss of function of the endogenous C9ORF72 protein product, RNA toxicity caused by RNA molecules or RNA foci that bind and sequester RNA-binding proteins or production of toxic dipeptide repeat proteins (DPR) by repeat-associated non-AUG initiated (RAN) translation of the repeat. In this thesis, we study RNA and DPR gain-of toxicity in vitro and in vivo models (zebrafish and mouse). We also characterize HR23B pathology in post-mortem brain sections of C9FTD/ALS patients. Our data mainly supports DPR toxicity. Identification of the pathological pathways underlying neurodegeneration could guide future research and lead to new treatments and is therefore of great importance for the FTD/ALS field.

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